Chronic respiratory diseases, such as COPD, asthma, and cystic fibrosis (CF), are the 3rd leading cause of death in the US, with costs exceeding $150B/year. A major obstacle to evaluate therapies for these diseases is that currently available tools to assess lung function are either insensitive to early disease or unsuitable for longitudinal use. Though ubiquitous, pulmonary function testing via spirometry is highly variable and insensitive to early and regional disease; bronchoscopy is insensitive to regional disease and invasive. While chest CT is sensitive to regional abnormalities, it provides little functional information, and radiation exposure limits its long- term and repeated use, particularly in children. An emerging solution to this pressing need is hyperpolarized (HP) 129Xe MRI, which provides quantitative markers of regional lung function. Currently, this technology is available only in larger research centers, primarily because it is regulated as a drug/device combination. Our long-term goal is to build a business that broadly deploys non-invasive, high-resolution HP 129Xe MRI to accel- erate treatment discovery and personalized care for lung diseases. The objective of this application is to estab- lish a marketable 129Xe hyperpolarizer and perform pediatric testing required by FDA for HP 129Xe approval and dissemination. To accomplish this objective, we will: 1) demonstrate the superior sensitivity of HP 129Xe MRI to conventional spirometry; 2) document human factors/usability studies and polarizer design under FDA-device control guidelines; and 3) demonstrate safety and utility in pediatric subjects, specifically CF patients. The ra- tionale for the project is that unlike other common chronic lung diseases, which have poorly understood dis- ease etiology and display variable disease trajectories and long time-courses, CF lung disease is caused by mutations in a single gene and displays predictable and rapid progression in adolescent CF patients, providing an ideal means to test HP 129Xe MRI against spirometry. Guided by our Phase I SBIR successes and strong preliminary data, we will accomplish these goals through three Specific Aims: 1) commission and operationally qualify a compact 129Xe hyperpolarizer; 2) demonstrate superior ability of HP 129Xe ventilation MRI to quantify 1-year lung function decline in adolescent CF patients, compared to spirometry; and 3) determine the contribu- tion of permanent airway remodeling to ventilation abnormalities. The proposed approach is innovative, be- cause it leverages improved polarization technology and end-user experience to obtain FDA mandated human factors data, meets FDA requirements for pediatric testing, and capitalizes on well-characterized decline in ad- olescent CF lung function. The proposed research is significant, because it will enable HP 129Xe technology that is easily disseminated, installed, and operated to be marketed to guide therapy development and patient treatment in all chronic lung diseases. Further, the proposed research has direct translational implications, be- cause it will provide much needed structure/function data to inform personalized care for pediatric CF patients.